Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:6][C:5]2[C@@:17]3([CH2:28][O:29][C:4]=2[CH:3]=1)[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]3.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>N1C(C)=CC(C)=CC=1C.C(Cl)Cl>[C:31](=[O:32])([O:33][CH2:34][CH3:35])[O:27][CH2:26][C@H:19]1[O:18][C@@:17]2([C:5]3[CH:6]=[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=4)[C:2]([Cl:1])=[CH:3][C:4]=3[O:29][CH2:28]2)[C@H:22]([OH:23])[C@@H:21]([OH:24])[C@@H:20]1[OH:25]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@]2(COc3cc(Cl)c(Cc4ccc(CC)cc4)cc32)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a solution of 30 (12 mg, 28.5 μmol) in 2,4,6-collidine (100 μL) at −30° C. was added a solution of ethyl chloroformate (4 μL, 41.8 umol, 1.5 eq.) in DCM (100 μL). The mixture was kept at −30° C. for 1.5 hours, warmed to ambient temperature, and stirred overnight, after which additional ethylchloroformate (4 μL) was added. The reaction mixture was quenched with methanol, evaporated, and purified via HPLC to give 31 (7.5 mg, 53% yield). 1H NMR (300 MHz, CD3OD) δ 7.14 (s, 1H), 7.07 (s, 4H), 6.83 (s, 1H), 4.68 (d, J=10.2 Hz, 1H), 4.57 (d, J=10.5 Hz, 1H), 4.36 (dd, J=2.1, 11.4 Hz, 1H), 4.21 (dd, J=5.1, 11.4 Hz, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.99 (s, 2H), 3.71 (d, J=9.6 Hz, 1H), 3.53-3.59 (m, 1H), 3.39 (t, J=8.7 Hz, 1H), 3.27-3.34 (m, 1H), 2.58 (q, J=7.5 Hz, 2H), 1.17-1.23 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:19]C(C)C)=[C:10]([S:15]([O-])(=O)=O)C=CC=2C)=[CH:4][CH:3]=1.[CH2:23]1COCC1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([CH3:19])[CH2:10][S:15][CH3:23])=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CC(C)C)c1-c1ccc(Cl)nc1
Reactant: C1CCOC1
Solvent: CCOCC
Product: CSCC(C)Cc1ccc(Cl)nc1
Temperature: 55 °C
Yield: 93 %

Procedure:
A solution 3-(6-chloropyridin-3-yl)-2-methylpropyl-4-methyl-benzenesulfonate (5.0 g, 14.7 mmol) and sodium methylthiolate (2.10 g, 30 mmol) in THF (50 mL) was stirred overnight at room temperature. The remaining unreacted starting material indicated on TLC was converted into the product completely after the solution was heated at 55° C. for 4 more hours. The mixture was diluted with ether and washed with 2 N NaOH solution (50 mL). The aqueous phase was washed with ether (50 mL). The combined organic phase was washed with brine (50 mL), dried over MgSO4, filtered and concentrated to give 2.94 g of the desired crude sulfide in 93% yield as a yellowish oil: M+=215, 217; δ 2.07 (s, 3H), 0.95 (d, 3H).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16](=[NH:20])OCC)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH2:26])[CH3:22]>C(O)C>[ClH:1].[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH:26][C:16]([C:14]1[O:15][C:11]([C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)=[NH:20])[CH3:22]
Reactant: CCOC(=N)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: CCOC(CN)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(CNC(=N)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1)OCC
Reaction time: 48 h
Yield: 30 %

Procedure:
A solution of 98 g (0.33 mole) of ethyl 5-(4-nitrophenyl)-2-furimidate hydrochloride and 48 g (0.36 mole) of aminoacetaldehyde diethyl acetal in 1500 ml of absolute ethanol was heated under reflux for 4 hr. After standing in a refrigerator for 2 days, the solid which was deposited was collected by filtration and washed with anhydrous ether to give 38 g (30%) of N-(2,2-diethoxyethyl)-5-(4-nitrophenyl)-2-furamidine hydrochloride. The filtrate was concentrated on a rotary evaporator. The solid which was deposited was collected by filtration and washed with anhydrous ether to give 34 g (57% total yield) of additional product, m.p. 220°-280° (dec.)
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22][Mg]Br>>[CH3:22][C@@H:8]1[CH:9]=[C:10]2[C@:15]([CH3:16])([CH2:14][CH2:13][C:12](=[O:20])[CH2:11]2)[C@@H:17]2[C@@H:7]1[C@H:6]1[C@@:2]([CH2:19][CH2:18]2)([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]1
Reactant: C[Mg]Br
Reactant: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@@H]1C=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
Alkylation of androsta-4,6-dien-3,17-dione 17 ketal 1 with methyl magnesium bromide in the presence of cuprous chloride, proceeds via conjugate addition to yield 7α-methylandrost-5-en-3,17-dione 17 ketal 2. Allylic bromination of 2 using N-bromosuccinimide in carbon tetrachloride yields the 6β-bromo-7α-methylandrost-4-en-3,17-dione 17 ketal 3. Lithium aluminum hydride reduction of the ketone in 3 with concomitant double bond migration and loss of bromide should yield 4. Deprotection of the C-17 ketone with aqueous acid yields 3β-hydroxy-7α-methylandrost-5-en-17-one, 5. Higher homologues may be synthesized using the substituted Grignard reagent i.e. R=CH3, C2H5, C3H7. The 7β-epimer can be synthesized by treatment of 2 with DDQ-dichlorodicyanoquinone to generate another olefin at C-7. Catalytic reduction of this olefin should occur from the α face of the steroid to yield the 7β-methyl steroid i.e. 7β-methylandrost-5-en-3,17-dione 17 ketal. Following the same sequence as above yields 3β-hydroxy-7β-methylandrost-5-en-17-one. ##STR20##
Reaction SMILES: ClC1C=CC=[C:4]([C:8](OO)=[O:9])C=1.C([C@@H:15]1[NH:18][C:17](=[O:19])[C@H:16]1[CH:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH3:21])(=O)C.S([O-])([O-])(=[O:32])=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:8]([O:19][C@@H:17]1[NH:18][C:15](=[O:32])[C@H:16]1[CH:20]([O:22][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25])[CH3:21])(=[O:9])[CH3:4]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)[C@@H]1NC(=O)[C@H]1C(C)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1C(C)O[Si](C)(C)C(C)(C)C
Reaction time: 15 h

Procedure:
m-Chloroperbenzoic acid (1 g) is added to a solution of trans-4-acetyl-3-[1-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone (0.23 g) in chloroform (15 ml), and the mixture is allowed to stand at room temperature for 15 hours and then poured into a mixture of ethyl acetate (100 ml), 5% aqueous sodium thiosulfate (50 ml) and aqueous sodium hydrogen carbonate (30 ml). The organic layer is separated, washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give 0.23 g of trans-4-acetoxy-3-[1-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[N:7]([CH2:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.[OH-:16].[Na+].[CH2:18]=O>>[OH:2][C:3]1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[N:7]([CH2:9][C:10]([F:11])([F:12])[F:13])[C:8]=1[CH2:18][OH:16]
Reactant: [OH-]
Reactant: Cc1cc(=O)c(O)cn1CC(F)(F)F
Reactant: C=O
Agent: Cl
Agent: [Na+]
Product: Cc1cc(=O)c(O)c(CO)n1CC(F)(F)F
Temperature: 40.5 °C
Reaction time: 11 h

Procedure:
5-Hydroxy-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one hydrochloride (4.87 g. 20.0 mmol) was mixed with 37% formaldehyde (30 mL) and 6N sodium hydroxide (7 mL, 42.0 mmol). The reaction mixture was stirred at 39-42° C. for 11 hours, and then additional 37% formaldehyde (30 mL) was added. The reaction mixture was stirred at 37° C. for 12 hours and then left at room temperature for a further 12 hours. The solid was filtered and the filtrate was acidified to pH about 5 to 6. The solution was concentrated with silica gel and the product was purified by column chromatography with a gradient mixture of 5-10% methanol in ethyl acetate as eluant to give the title compound 3-hydroxy-2-(hydroxymethyl)-6-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (3.02 g) as pale-peach solid. Yield 63.5%; 1H NMR (DMSO-D6+D2O, 90 MHz) δ (ppm): 6.20 (s, 1H), 5.15 (q, J=8.8 Hz, 2H), 4.33-4.92 (m, 2H) and 2.37 (s, 3H); MS m/z 238 [M+1]+.
Reaction SMILES: C(O[C:6]([C:8]1[CH:18]=[C:17]([O:19][CH:20]([CH3:22])[CH3:21])[C:11]2[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=2[CH:9]=1)=[O:7])(C)(C)C.[NH2:23][C:24]1[CH:28]=[CH:27][N:26]([CH3:29])[N:25]=1>>[CH3:29][N:26]1[CH:27]=[CH:28][C:24]([NH:23][C:6]([C:8]2[CH:18]=[C:17]([O:19][CH:20]([CH3:21])[CH3:22])[C:11]3[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=3[CH:9]=2)=[O:7])=[N:25]1
Reactant: CC(C)Oc1cc(C(=O)OC(C)(C)C)cc2c1CC(CO)O2
Reactant: Cn1ccc(N)n1
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(CO)O2

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 2-hydroxymethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (215a) and 3-amino-1-methyl-pyrazole. 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1 H) 7.26-7.35 (m, 1 H) 6.95-7.05 (m, 1H) 6.76-6.86 (m, 2 H) 4.93-5.08 (m, 1 H) 4.59-4.71 (m, 1 H) 3.84-3.91 (m, 1 H) 3.83 (s, 3 H), 3.22 (dd, J=16.42, 9.60 Hz, 1 H) 2.89-3.02 (m, 1 H) 1.98 (t, J=6.44 Hz, 1 H) 1.35 (d, J=6.06 Hz, 6 H); LCMS for C17H21N3O4 m/z 332.20 (M+H+).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[N:8]([CH2:12][CH2:13][NH:14][C:15](=O)[CH3:16])[CH:9]=[CH:10][CH:11]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>O.C(O)C>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH3:16][C:15]1[C:9]2[N:8]([C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=3)=[CH:11][CH:10]=2)[CH2:12][CH2:13][N:14]=1
Reactant: CC(=O)NCCn1cccc1-c1ccc(C)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CC1=NCCn2c1ccc2-c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
N-[2-(2-p-Tolylpyrrol-1-yl)ethyl]acetamide (3.9 g) was treated with 20 ml of phosphorus oxychloride under argon and boiled for 1/2 hour while stirring. The reaction mixture was hydrolyzed at 0° C. with 100 ml of 2N sodium hydroxide solution and 100 ml of 28% sodium hydroxide solution, diluted with 1000 ml of water and extracted with methylene chloride (1×200 ml, 2×100 ml). The organic extracts were combined, dried with MgSO4 and freed from solvent. 1.7 g of a total of 3.5 g of crude product were dissolved in a 25-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 1.8 g (68%) of 3,4-dihydro-1-methyl-6-p-tolylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 186°-189° C. (dec.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].C1(=O)N(CCS(Cl)(=O)=O)C(=O)C2=CC=CC=C12.N1C=CC=CC=1.[O:57]=[C:58]([S:72](Cl)(=[O:74])=[O:73])[CH2:59][N:60]1[C:64](=[O:65])[CH:63]2[C:66](=[O:70])[CH:67]=[CH:68][CH:69]=[C:62]2[C:61]1=[O:71]>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[S:72]([C:58](=[O:57])[CH2:59][N:60]1[C:64](=[O:65])[CH:63]2[C:66](=[O:70])[CH:67]=[CH:68][CH:69]=[C:62]2[C:61]1=[O:71])(=[O:73])=[O:74])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: O=C1C=CC=C2C(=O)N(CC(=O)S(=O)(=O)Cl)C(=O)C12
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)C(=O)CN1C(=O)C2=CC=CC(=O)C2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 8 ml of dichloromethane was treated with 0.287 g of 2-phthalimidoethanesulphonyl chloride and 0.1 ml of pyridine at room temperature under a nitrogen atmosphere. The mixture was stirred for 2 hours at room temperature and a further 0.287 g of 1,3-dioxo-2-phthalimidoethanesulphonyl chloride was added. The mixture was stirred overnight at room temperature and evaporated. The residue was dissolved in ethyl acetate and washed in sequence with water, 5% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate and evaporation gave a residue which was triturated with diethyl ether to give 0.47 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-(1,3-dioxo-2-phthalimidoethanesulphonyl)-4-methylvalerohydrazide in the form of a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:23](Cl)(=[O:25])=[O:24])([O-:13])=[O:12]>N1C=CC=CC=1>[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:23]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10])(=[O:25])=[O:24])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Cc1c(O)c(=O)ccn1C
Solvent: c1ccncc1
Product: Cc1c(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(=O)ccn1C
Yield: 23 %

Procedure:
3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.10 g, 0.73 mmol) was reacted with 2,4-dinitrobenzenesulfonyl chloride (0.3 g, 1.1 mmol) in 10 mL of pyridine to afford PZBG-3d in 23% yield (0.07 g, 0.2 mmol). 1H NMR (400 MHz, CDCl3) δ=8.83 (d, J=2.8 Hz 1H), 8.37 (dd, J1=9.6 Hz, J2=2.8 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 6.25 (d, J=7.6 Hz, 1H), 3.68 (s, 3H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ=169.35, 154.98, 144.00, 142.61, 141.42, 140.76, 138.54, 129.69, 122.24, 118.15, 116.78, 59.63, 13.29.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([NH2:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2].[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH:34]=O)([CH3:29])([CH3:28])[CH3:27].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([NH:11][CH2:34][CH2:33][NH:32][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:36])=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1NCCNC(=O)OC(C)(C)C
Reaction time: 23 h

Procedure:
To a solution of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (I-4a, 1.88 g, 5 mmol) and (2-oxo-ethyl)-carbamic acid tert-butyl ester (1590 mg, 10 mmol) in 1,2-dichloroethane (60 ml) at room temperature was added glacial acetic acid (858 microliters, 15 mmol) and NaBH(OAc)3 (2540 mg, 12 mmol). The reaction mixture was stirred for 23 hours, then additional (2-oxo-ethyl)-carbamic acid tert-butyl ester (500 mg, 3.14 mmol) and NaBH(OAc)3 (1000 mg, 4.7 mmol) were added. The reaction mixture was stirred for an additional 24 hours, quenched with 1 N NaOH, and diluted with CH2Cl2. The organic layer was separated and the aqueous layer extracted with CH2Cl2. The combined organic phases were washed with 0.5 M aqueous citric acid, 1 N NaOH, and saturated aqueous NaCl, dried, and concentrated in vacuo. The crude residue was purified on a Biotage 40+M column using CH2Cl2/MeOH (100:1) to give the desired product I-4b (900 mg): +ES MS (M+1) 519.5.
Reaction SMILES: [F-:1].[Cs+].C(O)(CC)(C)C.[F-].C[O-].[Na+].[OH:13][CH2:14][C:15]1([O:23][C@H:22]([CH2:24]O)[C@@H:20]([OH:21])[C@@H:18]1[OH:19])[O:16]C>>[F:1][CH2:24][C@@H:22]([OH:23])[C@@H:20]([OH:21])[C@H:18]([OH:19])[C:15](=[O:16])[CH2:14][OH:13]
Reactant: COC1(CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: [F-]
Agent: C[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CF

Procedure:
As a starting material, D-fructose is inexpensive and readily available. Briefly, treatment of fructose with acidic methanol affords a mixture of methyl α/β-D-fructofuranosides (II, III) which may be separated using standard silica gel chromatography or, alternatively, carried on as a mixture (FIG. 1). Selective protection of the primary C-6 hydroxyl with tert-butyldimethylchlorosilane (TBDMSCl) in pyridine, followed by global acetylation produces intermediate (V) in moderate yield over the two steps. The silyl protecting group is removed by treatment with aqueous trifluoroacetic acid in dichloromethane to provide intermediate (VI) in 91% (Tatibouet et al., 2000). Compound (VI) is then fluorinated via triflation under standard conditions and immediate treatment with three equivalents of cesium fluoride in refluxing tert-amyl alcohol (Kim et al., 2006). The quick and clean fluoride displacement reaction is useful for installation of [18F] for imaging experiments. Standard deprotection of the acetates using sodium methoxide followed by acidic hydrolysis of the methyl fructofuranoside provides 6-deoxy-6-fluoro-D-fructose (IX) as a white solid in 62% (two steps).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][O-:4].[F:7][C:8]([F:12])([F:11])[CH2:9][O-:10].C([Al+2:15])C.[F:16][C:17]([F:21])([F:20])[CH2:18][OH:19].[Al]>C(Cl)Cl>[F:1][C:2]([F:6])([F:5])[CH2:3][O-:4].[F:7][C:8]([F:12])([F:11])[CH2:9][O-:10].[F:16][C:17]([F:21])([F:20])[CH2:18][O-:19].[Al+3:15]
Reactant: OCC(F)(F)F
Reactant: CC[Al+2]
Agent: [Al]
Agent: [O-]CC(F)(F)F
Solvent: ClCCl
Product: [Al+3]
Temperature: 40 °C
Reaction time: 1 h

Procedure:
In a flask, under a nitrogen blanket, were placed 7.43 g (0.29 mole) of the product of Example 2 and 50 ml methylene chloride. Then, 3.07 g (0.031 mole) of 2,2,2-trifluoroethanol was added in a way so as to maintain the temperature at about 40° C. After the addition was complete, the flask was placed in an oil bath at 60° C. and most of the methylene chloride was evaporated. The product was allowed to stand at the same temperature for one hour and the remainder of the solvent stripped off under vacuum. There was obtained 9.09 g (95% of theoretical yield) of a white crystalline solid. Analysis for aluminum showed 8.36% Al. The theoretical value was 8.33%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl[C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.O>[F:16][C:15]([F:18])([F:17])[C:14]1[C:9]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: O=C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C1CN(c2ncccc2C(F)(F)F)CCN1
Temperature: 120 °C

Procedure:
A mixture of piperazin-2-one (4.85 g, 48.47 mmol, Avocado Research), 2-chloro-3-trifluoromethyl-pyridine (8.8 g, 48.47 mmol, TCI America) and diisopropylethylamine (111 mL, 58.16 mmol, Aldrich) in DMSO (160 mL) was heated at 120° C. for 16 h. The mixture was cooled to room temperature, diluted with H2O (500 mL) and extracted with EtOAc (2×500 mL). The combined organic extracts were dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with dichloromethane/MeOH (15:1) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 206 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1>>[NH:19]1[C:27]2[C:22](=[C:23]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)[N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[N:20]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: CN1CCN(c2nc(Cl)nc3c2cnn3C)CC1
Product: CN1CCN(c2nc(-c3cccc4[nH]ncc34)nc3c2cnn3C)CC1

Procedure:
6-Chloro-1-methyl-4-(4-methyl-piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine was reacted with indazole boronic acid pinacol ester using General Procedure A. Purification on silica yielded 148. NMR (CDCl3): 2.41 (3H, s), 2.60-2.66 (4H, m), 4.15-4.19 (7H, m), 7.50-7.53 (1H, m), 7.61 (1H, d), 8.00 (1H, s), 8.41 (1H, d), 9.13 (1H, s). MS: (ESI+) MH+=349
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:29]>>[ClH:29].[C:1]1([CH2:7][CH2:8][C:9]2[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:26]=3[N:18]([CH2:19][CH2:20]4)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(CCc1ccccc1)Nc1ccccc1N1CCc2ccccc21
Product: Cl
Product: c1ccc(CCC2=Nc3ccccc3N3CCc4cccc2c43)cc1
Temperature: 25 °C
Reaction time: 9.5 h

Procedure:
A rapidly stirred solution of 52.65 g of 1-[2-(3-phenyl-1-oxo-propyl)aminophenyl]indoline in 200 ml POCl3 under N2 is slowly brought to 105°-115° C. After 9.5 hours, the mixture is permitted to cool to room temperature for over 48 hours. The excess POCl3 is distilled at aspirator pressure (bath temperature 55°-60° C.) to yield a solid which is triturated with hexane, filtered, washed with additional hexane, and dried at room temperature under high vacuum to yield 1,2-dihydro-6-(2-phenylethyl)-indolo[1,7-ab][1,5]benzodiazepine hydrochloride, m.p. 181.5°-183.0° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.ClCCl>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: CN1CCC(=O)CC1
Reactant: NCc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(NCc2ccc(Cl)cc2)CC1

Procedure:
1-Methyl-4-piperidone (566 mg, 5.0 mmol) was dissolved in 10 ml methanol and placed in 100 ml flask. 4-Chlorobenzylamine (708 mg, 5.0 mmol) was added. Mixture was stirred and Acetic acid (˜0.75 ml) was added until pH˜5. NaCNBH3 (628 mg, 10 mmol) was slowly added. Gas evolution observed. After magnetic stirring for 16 hrs methanol was partly removed on Rotavapor (40° C.). Dichloromethane, 2M NaOH and water were added until pH˜10. Phases were separated and aq. phase was then re-extracted with dichloromethane. Combined organic phases were dried over MgSO4. Concentration on Rotavapor (40° C.) yielded 1.14 g crude 47AKU-27. TLC (10% methanol in dichloromethane): Rf=0.3. HPLC-MS (Method A): M+=239.1 (MS(%)=96).